Tissue surfaces need protection depending on the type and extent of chemical exposure and wearing that they normally are subjected to. All cells in the body are thus covered by a cell membrane bilayer that mainly consists of lipids and proteins. Epithelial surfaces, which connect to the exterior world; the respiratory, gastrointestinal, and to some extent also the genitourinary tracts, are exposed to a rather harsh environment. These epithelial surfaces are further covered by a mucus layer having viscoelastic and pronounced protecting properties. Tissues such as synovia and mesothelium, on the other hand, are not protected by mucus since they are not exposed to drastic condition of the same magnitude.
In addition, the vital epithelial tissues, such as blood vessels or blood organs, are coated with mucous, serous, synovial and endothelial membranes so that they can function independently of each other. The peritoneal, pericardial and pleural membranes consist of a single layer of mesothelial cells, which is covered by a thin film of peritoneal fluid. The components of the membranes as well as the covering layer of fluid have several functions, e.g. lubrication of the enclosed organs.
The protective epithelial membrane is very thin and comprises a delicate layer of connective tissue covered with a monolayer of mesothelial cells and only one or a few bilayers of phospholipids. This makes the synovia and mesothelium tissue especially vulnerable to infection and trauma. When such a membrane is exposed to a physical, chemical or microbial challenge, many potent substances, which are harmful to the membrane, are often released in response thereto. The structure and function of the membrane is consequently easily destroyed in connection with trauma, ischemia, and infection. After an irritation of the stress-sensitive membrane, e.g. only by the desiccation or abrasion of the membrane surfaces during surgery, it will rapidly be covered with a fibrin clot. Since the plasminogen activating activity (i.e. the fibrinolytic capacity) is reduced after trauma, the fibrin clots will later on become organised as fibrous adhesions, i.e. small bands or structures, by which adjacent serous or synovial membranes adhere in an abnormal way. Surgical operations, infection or inflammation in those parts of the body, which are coated with serous or synovial membranes, can result in adhesive inflammation regardless of the size of the affected area. The adhesions between vital epithelial tissues are formed within the first few days following surgery trauma or infection and may be observed not only in particular portions of the body but in all vital tissues. Such adhesions between for example contact zones between intestines or between intestines and the abdominal wall are the result of the often unnoticed tissue damage as desiccation and they occur for various reasons, including mechanical and chemical stimulation of vital tissues accompanying surgical manipulations, postoperative bacterial infection, inflammation or further complications. Adhesion of vital epithelial tissues, large or small, may be observed in most surgical fields. It has been reported that of all patients undergoing abdominal surgery at one hospital over a four-year period, 93% were found to have adhesions from previous operations. In addition, in a 10 year period there will be a need of adhesion prevention in about 20% of all surgical operations, which corresponds to more than 1 million operations annually on each major continent.
However, the obtained postsurgical adhesions are the result of a natural wound healing response of tissue damage occurring during surgery. Numerous factors play a role in peritoneal wound healing and the development of adhesions. Among others are peritoneal macrophages known to have an important role in initial peritoneal repair.
Thus, while waiting after surgery for the body to produce new protective layers it is desired to supply the corresponding protection from the outside to exposed epithelial surfaces in an effective way. Furthermore, it is important to prevent or reduce the infection and/or the inflammation obtained after surgery as well as the accompanying fibrin formation.
Various bioactive materials and macromolecules have been reported to decrease the extent of postoperative abdominal adhesions. Likewise, a number of methods for limiting the formation of surgical adhesion have been studied with some encouraging but often ambiguous results. However, most efforts made to avoid or reduce postoperative peritoneal adhesions have finally been abandoned. Among the methods used prevention of fibrin formation, reduction of fibrin formation, surface separation, and surgical techniques can be mentioned.
Numerous investigations have been carried out in which barriers are placed at a site of injury in order to prevent fibrin bridge formation between the injured tissue and neighboring organs. Such barriers include resorbable materials, such as enzymatically degradable oxidized regenerated cellulose, and slowly dissolving physiochemically crosslinked hydrogels of the Pluronic™ type.
Most methods of surface protection of exposed epithelial surfaces, whereby a postsurgical adhesion formation is limited, have also focused on providing wound separation by placing a material between the tissues. In addition, several types of viscous polymer solutions such as polyvinylpyrrolidone, sodium carboxymethyl cellulose, dextrans, and hyaluronic acid have been added before and/or at the end of surgery in order to control the wound healing events after the occurrence of the presumed tissue injuries. These solutions are supposed to act by increasing the lubrication and preventing the fibrin clots from adhering to other surfaces or by mechanically separating damaged tissues while they heal.
The employed polymeric solutions are mainly based on the viscosity of the high molecular weight polymer, which is intended to increase with increasing concentration. The polymer is often a polysaccharide as in U.S. Pat. No. 4,994,277, in which a viscoelastic gel of biodegradable xanthan gum in a water solution for preventing adhesions between vital tissues is described. However, the major disadvantage of these polymers, when used for reducing for example peritoneal adhesions as protective coatings during surgery or surface separation agents after surgery, is that they do not significantly reduce adhesions because of their short residence time in the peritoneal cavity. The result is that subsequent surgeries have to be performed on the patient. Less viscous polymer solutions have been used as a tissue protective coating during surgery in order to maintain the natural lubricity of tissues and organs and to protect the enclosing membrane. Precoating for tissue protection and adhesion prevention includes coating tissues at the beginning of surgery before a significant tissue manipulation and irritation can occur and continuously throughout the operation so that a protective coating can be maintained on the tissues.
U.S. Pat. No. 5,366,964 shows a surgical viscoelastic solution for promoting wound healing, which is used in direct contact with cells undergoing wound healing. The solution is intended for cell protection and cell coating during surgery and comprises one or several polymeric components. Hydroxypropylmethyl cellulose and chondroitin sulphate are supposed to lubricate the tissue, while sodium hyaluronate would provide viscoelastic properties to the solution. Several agents of today for treating postsurgical adhesions contain hyaluronic acid. For example U.S. Pat. No. 5,409,904 describes solutions which reduce cell loss and tissue damage intended for protecting endothelial cells during ophthalmic surgery. The compositions used are composed of a viscoelastic material comprising hyaluronic acid, chondroitin sulphate, modified collagen, and/or modified cellulose. In WO 9010031 a composition is described for preventing tissue adhesion after surgery containing dextran and hyaluronic acid in which the substances are supposed to act synergistically. In WO 9707833 a barrier material for preventing surgical adhesions is shown, which comprises benzyl esters or covalently crosslinked derivatives of hyaluronic acid.
A hyaluronic acid based agent manufactured by Pharmacia under the trademark Healon and originally intended as an intraocular instillation has been found to be the most effective agent up to now. However, hyaluronic acid is isolated from cock's crests and is thus very expensive as well as potentially allergenic even in small quantities and even more for large surfaces such as the peritoneum which has an area of about two m2.
In WO 9903481 a composition for lubricating and separating tissues and biological membranes from adjacent membranes or adjacent cells or tissues is shown, which comprises a hydrophobic polymer formed from a biologically acceptable water-soluble cationic polymer carrying covalently bound hydrophobic groups.
Likewise, water-insoluble biocompatible compositions are shown in EP 0,705,878, which comprise a polyanionic polysaccharide combined with a hydrophobic bio-absorbable polymer.
In U.S. Pat. No. 6,235,313 a variety of polymers were compared for adhesive force to mucosa surfaces. Negatively charged hydrogels, such as alginate and carboxymethyl cellulose, with exposed carboxylic groups on the surface, were tested, as well as some positively-charged hydrogels, such as chitosan. The choice was based on the fact that most cell membranes are actually negatively charged. However, there is still no definite conclusion as to what the most important property is in order to obtain good bioadhesion to the wall of the gastrointestinal tract. For example, chitosan is considered to bind to a membrane by means of ionic interactions between positively charged amino groups on the polymer and negatively charged sialic acid groups on the membrane. Thus, polycationic molecules, such as chitosan and polylysine, have a strong tendency to bind to exposed epithelial surfaces since these generally have a negative net charge.
A main drawback of both these cationic molecules is that they exhibit toxic effects. For example, polylysine is considered to act as an inhibitor of the calcium channel by producing a conformational change, thereby inhibiting transmembrane ion fluxes.